In the United States, over 80% of prostate cancer patients die with bone metastases. Second line hormonal therapies such as enzalutamide only improve overall patient survival by a few months in about 50% of the patients, and almost all patients develop drug resistance. Thus, there is an urgent need to determine the mechanisms of drug resistance and to develop new approaches for overcoming such resistance and for better treatment of prostate cancer bone metastasis. Enzalutamide is a small-molecule inhibitor of the androgen receptor (AR). Our preliminary study demonstrated that although enzalutamide inhibited the tumor growth of castration-resistant prostate cancer C4-2B cells when xenografted orthotopically or subcutaneously, it had no effect on the growth of C4-2B tumors in the bone and the development of bone lesions. This data highlights a crucial role of the microenvironment in enzalutamide resistance in prostate cancer bone metastasis. Interestingly, we found that enzalutamide significantly and specifically reduced the TGF-? type II receptor (TGFBR2) protein in osteoblasts. This observation was also confirmed in prostate cancer patients who had undergone the second line hormonal therapies such as enzalutamide. To determine the role of TGFBR2 in the osteoblasts during bone metastasis, we used a mouse model (Tgfbr2Col1CreERT KO) with inducible Tgfbr2 knockout specifically in the osteoblasts. We found that Tgfbr2 KO in osteoblasts significantly promoted prostate cancer bone metastasis. Based on these results, we hypothesize that reduction of TGFBR2 in osteoblasts caused by enzalutamide results in resistance to the drug in prostate cancer bone metastasis. The objectives of this proposal are to determine how enzalutamide decreases osteoblast TGFBR2 and thus promotes prostate cancer bone metastasis and to identify novel approaches to counteracting the enzalutamide resistance.